3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors

ABSTRACT

The present invention relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with HDAC6, having a Formula I: 
                         
where R, L, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , and Y 4  are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Non-Provisional Application No.16/222,871, filed on Dec. 17, 2018, which is a divisional of U.S.Non-Provisional Application No.16/133,918, filed Sep. 18, 2018, which isa divisional of U.S. Non-Provisional Application No. 15/013,826, filedFeb. 2, 2016, which claims the benefit of priority of U.S. ProvisionalApplication No. 62/110,716, filed Feb. 2, 2015 and U.S. ProvisionalApplication No. 62/205,438, filed Aug. 14, 2015, each of which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to inhibitors of zinc-dependent histonedeacetylases (HDACs) useful in the treatment of diseases or disordersassociated with HDACs including cell proliferation diseases (e.g.,cancer), neurological and inflammatory diseases. Specifically, thisinvention is concerned with compounds and compositions inhibiting HDACs,methods of treating diseases associated with HDACs, and methods ofsynthesizing these compounds.

BACKGROUND OF THE INVENTION

Many members of the HDAC family require zinc (Zn) to function properly.For instance, the isozyme histone deacetylase 6 (HDAC6) is azinc-dependent histone deacetylase that possesses histone deacetylaseactivity. Other family members include HDACs 1-5 and 7-11. (De Ruijteret al, Biochem. J. 2003. 370; 737-749).

HDAC6 is known to deacetylate and associate with α-tubulin, cortactin,heat shock protein 90, β-catenin, glucose-regulated protein 78 kDa,myosin heavy chain 9, heat shock cognate protein 70, and dnaJ homologsubfamily A member 1 (reviewed in Li et al, FEBS J. 2013, 280: 775-93;Zhang et al, Protein Cell. 2015, 6(1): 42-54). Diseases in which HDAC6inhibition could have a potential benefit include cancer (reviewed inAldana-Masangkay et al, J. Biomed. Biotechnol. 2011, 875824),specifically: multiple myeloma (Hideshima et al, Proc. Natl. Acad. Sci.USA 2005, 102(24):8567-8572); lung cancer (Kamemura et al, Biochem.Biophys. Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro etal, Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et al,Cancer Res. 2008, 68(18):7561-7569; Park et al, Oncol. Rep. 2011, 25:1677-81; Rey et al, Eur. J Cell Biol. 2011, 90: 128-35); prostate cancer(Seidel et al, Biochem Pharmacol. 2015 (15)00714-5); pancreatic cancer(Nawrocki et al, Cancer Res. 2006, 66(7):3773-3781); renal cancer (Chaet al, Clin. Cancer Res. 2009, 15(3): 840-850); hepatocellular cancer(Ding et al, FEBS Lett. 2013, 587:880-6; Kanno et al, Oncol. Rep. 2012,28: 867-73); lymphomas (Ding et al, Cancer Cell Int. 2014, 14:139;Amengual et al, Clin. Cancer Res. 2015, 21(20):4663-75); and leukemiassuch as acute myeloid leukemia (AML) (Fiskus et al, Blood 2008,112(7):2896-2905) and acute lymphoblastic leukemia (ALL)(Rodriguez-Gonzalez et al, Blood 2008, 112(11): Abstract 1923)).

Inhibition of HDAC6 may also have a role in cardiovascular disease,including pressure overload, chronic ischemia, andinfarction-reperfusion injury (Tannous et al, Circulation 2008, 117(24):3070-3078); bacterial infection, including those caused byuropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008,284(1):446-454); neurological diseases caused by accumulation ofintracellular protein aggregates such as Alzheimer's, Parkinson's andHuntington's disease (reviewed in Simoes-Pires et al, Mol. Neurodegener.2013, 8: 7) or central nervous system trauma caused by tissue injury,oxidative-stress induced neuronal or axomal degeneration (Rivieccio etal, Proc. Natl. Acad. Sci. USA 2009, 106(46):19599-195604); andinflammation and autoimmune diseases through enhanced T cell-mediatedimmune tolerance at least in part through effects on regulatory T cells,including rheumatoid arthritis, psoriasis, spondylitis arthritis,psoriatic arthritis, multiple sclerosis, lupus, colitis and graft versushost disease (reviewed in Wang et al, Nat. Rev. Drug Disc. 20098(12):969-981; Vishwakarma et al, Int. Immunopharmacol. 2013, 16:72-8;Kalin et al, J. Med. Chem. 2012, 55:639-51); and fibrotic disease,including kidney fibrosis (Choi et al, Vascul. Pharmacol. 201572:130-140).

Four HDAC inhibitors are currently approved for the treatment of somecancers. These are suberanilohydroxamic acid (Vorinostat; Zolinza®) forthe treatment of cutaneous T cell lymphoma and multiple myeloma;Romidepsin (FK228; FR901228; Istodax®) for the treatment of peripheral Tcell lymphoma; Panobinostat (LBH-589; Farydak®) for the treatment ofmultiple myeloma; and belinostat (PXD101; Beleodaq®) for the treatmentof peripheral T cell lymphoma. However, these drugs are of limitedeffectiveness and can give rise to unwanted side effects. Thus there isa need for drugs with an improved safety-efficacy profile.

Given the complex function of HDAC6 and their potential utility in thetreatment of proliferative diseases, neurological diseases, andinflammatory diseases, there is a need for HDAC inhibitors (e.g., HDAC6inhibitors) with good therapeutic properties.

SUMMARY OF THE INVENTION

One aspect of the invention relates to compounds of Formula I:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers and isomers thereof,

wherein:

X¹ is independently CR¹R², NR³, O, or C═O;

X² and X⁴ are each independently CR¹R², C═O, S(O) or SO₂;

X³ is CR^(1′)R^(2′); wherein X⁴, X², and X¹ are not all simultaneouslyCR¹R²;

Y¹ and Y⁴ are not bonded to —C(O)NHOH and are each independently N orCR¹;

Y² and Y³ are each independently N or CR¹ when not bonded to —C(O)NHOHand Y² and Y³ are C when bonded to —C(O)NHOH;

L is a bond, —(CR¹R²)_(n)—, —C(O)O—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—,—S(O)—, or —S(O)NR³—, wherein L is bound to the ring nitrogen throughthe carbonyl or sulfonyl group;

R is independently —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, —C₅-C₁₂ spirocycle,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1 to 5heteroatoms selected from the group consisting of N, S, P, and O,wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl,spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more —OH, halogen, oxo, —NO₂, —CN,—R¹, —R², —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹,—NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, orheteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O;

each R¹ and R² are independently, and at each occurrence, —H, —R³, —R⁴,—C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl,—C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5heteroatoms selected from the group consisting of N, S, P, and O, —OH,halogen, —NO₂, —CN, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆ alkyl), —(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, or —(CHR⁵)_(n)NR³R⁴, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more substituentsselected from —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, NR³R⁴,—S(O)₂N(R³)₂—, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,—S(O)NR³R⁴, —NR³S(O)R⁵, heterocycle, aryl, and heteroaryl containing 1to 5 heteroatoms selected from the group consisting of N, S, P, and O;

or R¹ and R² can combine with the atom to which they are both attachedto form a spirocycle, spiroheterocycle, or a spirocycloalkenyl;

or R¹ and R², when on adjacent atoms, can combine to form a heterocycle,cycloalkyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected fromthe group consisting of N, S, P, and O, or cycloalkenyl;

or R¹ and R², when on non-adjacent atoms, can combine to form a bridgingcycloalkyl, cycloalkenyl, or heterocycloalkyl;

R^(1′) and R^(2′) are independently, and at each occurrence, H, aryl, orheteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O, wherein each aryl or heteroaryl isoptionally substituted with one or more substituents selected from —OH,halogen, —NO₂, oxo, —CN, —R³, —R⁵, —OR³, —NHR³, —NR³R⁴, —S(O)₂N(R³)₂,—S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵,heterocycle, aryl, and heteroaryl containing 1 to 5 heteroatoms selectedfrom the group consisting of N, S, P, and O, wherein at least one ofR^(1′) or R^(2′) is not H;

R³ and R⁴ are independently, and at each occurrence, —H, —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selectedfrom the group consisting of N, S, P, and O, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂(C₁-C₆ alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆alkyl, or —(CHR⁵)_(n)N(C₁-C₆ alkyl)₂, wherein each alkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more substituents selected from —OH,halogen, —NO₂, Oxo, —CN, —R⁵, —O(C₁-C₆) alkyl, —NH(C₁-C₆) alkyl,—N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NHC₁-C₆ alkyl, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —S(O)R⁵,—S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)R⁵, heterocycle, aryl, andheteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O;

or R³ and R can combine with the nitrogen atom to which they areattached to form a heterocycle or heteroaryl containing 1 to 5heteroatoms selected from the group consisting of N, S, P, and O,wherein each heterocycle or heteroaryl is optionally substituted with—R⁴, —OR⁴, or —NR⁴R⁵;

R⁵ is independently, and at each occurrence, —H, —C₁-C₆ alkyl, —C₂-C₆alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selectedfrom the group consisting of N, S, P, and O, —OH, halogen, —NO₂, —CN,—NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆ alkyl, —S(O)(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆ alkyl) or —(CH₂)_(n)N(C₁-C₆ alkyl)₂; and

each n is independently and at each occurrence an integer from 0 to 6;and

provided that when X² and X⁴ are both C═O, X¹ is not NR³.

Another aspect of the invention relates to a method of treating adisease or disorder associated with HDAC6 modulation in a subject inneed thereof, comprising administering to the subject an effectiveamount of a compound of Formula I.

Another aspect of the invention is directed to a method of inhibitingHDAC6. The method involves administering to a patient in need thereof aneffective amount of a compound of Formula I.

Another aspect of the disclosure relates to a compound of Formula I, ora pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer,or isomer thereof, for use in treating or preventing a diseaseassociated with HDAC6 modulation.

Another aspect of the disclosure relates to the use of a compound ofFormula I, or a pharmaceutically acceptable salt, prodrug, solvate,hydrate, tautomer, or isomer thereof, in the manufacture of a medicamentfor treating or preventing a disease associated with HDAC6 modulation.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutically acceptable carrier can furtherinclude an excipient, diluent, or surfactant. The pharmaceuticalcomposition can be effective for treating a disease or disorderassociated with HDAC6 modulation in a subject in need thereof. Thepharmaceutical compositions can comprise the compounds of the presentinvention for use in treating diseases described herein. Thecompositions can contain at least one compound of the invention and apharmaceutically acceptable carrier. The invention also provides the useof the compounds described herein in the manufacture of a medicament forthe treatment of a disease associated with HDACs.

The present invention also provides methods for the treatment of humandiseases or disorders including, without limitation, oncological,neurological, inflammatory, autoimmune, infectious, metabolic,hematologic, or cardiovascular diseases or disorders.

The present invention also provides compounds that are useful ininhibiting of zinc-dependent HDAC enzymes, and in particular HDAC6.These compounds can also be useful in the treatment of diseasesincluding cancer.

The present invention further provides compounds that can inhibit HDAC6.In some embodiments, the efficacy-safety profile of the compounds of thecurrent invention can be improved relative to other known HDAC (e.g.,HDAC6) inhibitors. Additionally, the present technology also has theadvantage of being able to be used for a number of different types ofdiseases, including cancer and non-cancer indications. Additionalfeatures and advantages of the present technology will be apparent toone of skill in the art upon reading the Detailed Description of theInvention, below.

DETAILED DESCRIPTION OF THE INVENTION

HDAC6 is a zinc-dependent histone deacetylase that has two catalyticdomains. HDAC6 can interact with and deacetylate non-histone proteins,including HSP90 and α-tubulin. Acetylation of HSP90 is associated withloss of function of HSP90. HDAC6 is also implicated in the degradationof misfolded proteins as part of the aggresome. Accordingly, inhibitionof HDAC6 can have downstream effects that can play a role in thedevelopment of certain diseases such as cancer. The present inventionprovides inhibitors of HDAC6 and methods for using the same to treatdisease.

In a first aspect of the invention, compounds of the Formula I aredescribed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, and isomers thereof, wherein R, L, X¹, X², X³, X⁴, Y¹, Y²,Y³, and Y⁴ are described as above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

DEFINITIONS

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (e.g., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (e.g., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have1 to 2 aromatic rings, including monocyclic or bicyclic groups such asphenyl, biphenyl or naphthyl. Where containing two aromatic rings(bicyclic, etc.), the aromatic rings of the aryl group may be joined ata single point (e.g., biphenyl), or fused (e.g., naphthyl). The arylgroup may be optionally substituted with one or more substituents, e.g.,1 to 5 substituents, at any point of attachment. Exemplary substituentsinclude, but are not limited to, —H, -halogen, —O—C₁-C₆ alkyl, —C₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,—OH, —OP(O)(OH)₂, —OC(O)C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —OC(O)OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —S(O)₂—C₁-C₆ alkyl,—S(O)NHC₁-C₆ alkyl, and —S(O)N(C₁-C₆ alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include indanyl, indenyl,tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, S, P, and O, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, S, P, and O. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl,benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

“Alkyl” refers to a straight or branched chain saturated hydrocarbon.C₁-C₆ alkyl groups contain 1 to 6 carbon atoms. Examples of a C₁-C₆alkyl group include, but are not limited to, methyl, ethyl, propyl,butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyland neopentyl.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Alkenyl groups can have 2to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl, or propyl are attached to alinear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. A C₂-C₆ alkenyl group is an alkenylgroup containing between 2 and 6 carbon atoms.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Alkynyl groups can have 2to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl, or propyl are attached to alinear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C₂-C₆alkynyl group is an alkynyl group containing between 2 and 6 carbonatoms.

The term “cycloalkyl” means monocyclic or polycyclic saturated carbonrings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is acycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkylgroup can be fused (e.g., decalin) or bridged (e.g., norbornane).

The term “cycloalkenyl” means monocyclic, non-aromatic unsaturatedcarbon rings containing 3-18 carbon atoms. Examples of cycloalkenylgroups include, without limitation, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and norborenyl. A C₃-C₈ cycloalkenyl is acycloalkenyl group containing between 3 and 8 carbon atoms.

The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer tomonocyclic or polycyclic 3 to 24-membered rings containing carbon andheteroatoms taken from oxygen, nitrogen, or sulfur and wherein there isnot delocalized π electrons (aromaticity) shared among the ring carbonor heteroatoms. Heterocyclyl rings include, but are not limited to,oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.A heterocyclyl or heterocycloalkyl ring can also be fused or bridged,e.g., can be a bicyclic ring.

As used herein, the term “halo” or “halogen” means fluoro, chloro,bromo, or iodo.

The term “carbonyl” refers to a functional group composing a carbon atomdouble-bonded to an oxygen atom. It can be abbreviated herein as “oxo”,as C(O), or as C═O.

“Spirocycle” or “spirocyclic” means carbogenic bicyclic ring systemswith both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spirohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A C₃-C₁₂spirocycle is a spirocycle containing between 3 and 12 carbon atoms. Oneor more of the carbon atoms can be substituted with a heteroatom.

The term “spirocyclic heterocycle” or “spiroheterocycle” is understoodto mean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl).

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, decollate,tosylate, triethiodide, and valerate salts.

The term “stereoisomers” refers to the set of compounds which have thesame number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” refers to any member of this set of compounds.

The term “diastereomers” refers to the set of stereoisomers which cannotbe made superimposable by rotation around single bonds. For example,cis- and trans-double bonds, endo- and exo-substitution on bicyclic ringsystems, and compounds containing multiple stereogenic centers withdifferent relative configurations are considered to be diastereomers.The term “diastereomer” refers to any member of this set of compounds.In some examples presented, the synthetic route may produce a singlediastereomer or a mixture of diastereomers. In some cases thesediastereomers were separated and in other cases a wavy bond is used toindicate the structural element where configuration is variable.

The term “enantiomers” refers to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”refers to a single member of this pair of stereoisomers. The term“racemic” refers to a 1:1 mixture of a pair of enantiomers.

The term “tautomers” refers to a set of compounds that have the samenumber and type of atoms, but differ in bond connectivity and are inequilibrium with one another. A “tautomer” is a single member of thisset of compounds. Typically a single tautomer is drawn but it isunderstood that this single structure is meant to represent all possibletautomers that might exist. Examples include enol-ketone tautomerism.When a ketone is drawn it is understood that both the enol and ketoneforms are part of the invention.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound. Furthermore, as used herein a prodrug is a drugwhich is inactive in the body, but is transformed in the body typicallyeither during absorption or after absorption from the gastrointestinaltract into the active compound. The conversion of the prodrug into theactive compound in the body may be done chemically or biologically(e.g., using an enzyme).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula I may have one or moreasymmetric carbon atom and may occur as racemates, racemic mixtures andas individual enantiomers or diastereomers.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

In another embodiment of the invention are described compounds of theFormula IA:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers or isomer thereof; where R, L, X¹, X², X³, X⁴, Y¹, Y³, and Y⁴are defined as above in Formula I.

In another embodiment of the compounds of Formula IA, X⁴ is CR¹R².

In another embodiment of the compounds of Formula IA, X¹ is NR³, O, orC═O.

In another embodiment of the compounds of Formula IA, X¹ is O.

In another embodiment of the compounds of Formula IA, X¹ is O and X⁴ isCR¹R².

In some embodiments of the invention, the compounds of Formula IA may beof the Formula IA-1.

For instance, in some embodiments of Formula IA-1, the compounds can beof the Formula IA-1a, Formula IA-1b, or Formula IA-1c:

In other embodiments of the compounds of Formula IA, the compound is ofthe Formula IA-2:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-3:

In yet other embodiments of the compounds of Formula IA, the compound isof the Formula IA-4:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-5:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-6:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-7:

In other embodiments of the compounds of Formula IA, the compound is ofthe Formula IA-8:

In a further embodiment of the compounds of Formula IA, the compound isalso of the Formula IA-9:

In another embodiment of the compounds of Formula IA, the compound is ofthe Formula IA-10:

In another embodiment of the compounds of Formula IA, the compound is ofthe Formula IA-11:

In one embodiment of the invention are also disclosed compounds of theFormula IB:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,enantiomers and isomers thereof where R, L, X¹, X², X³, X⁴, Y¹, Y², andY⁴ are defined as above in Formula I.

In one embodiment of the compounds of Formula IB, X⁴ is CR¹R².

In another embodiment of the compounds of Formula IB, X¹ is NR³, O, orC═O.

In another embodiment of the compounds of Formula IB, X¹ is O.

In another embodiment of the compounds of Formula IB, X¹ is O and X⁴ isCR¹R².

In another embodiment of the compounds of Formula IB, X¹ is N, X² isC═O, and X⁴ is CR¹R².

In some embodiments of the invention, the compounds of Formula IB, maybe of the Formula IB-1:

In yet other embodiments of the compounds of Formula IB, the compound isof the Formula (IB-2):

In other embodiments of the compounds of Formula IB, the compound mayalso be of the Formula IB-3:

In other embodiments of the compounds of Formula IB, the compound is ofthe Formula (IB-4):

In a further embodiment of the compounds of Formula IB, the compound isalso of the Formula IB-5:

In some embodiments of Formula (I), X¹ is O. In another embodiment, X¹is O and X² is CR¹R². In yet another embodiment, X¹ is O, X² is CR¹R²,and X³ is CR^(1′)R^(2′.) In another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′,) and X⁴ is CR¹R². In yet another embodiment, X¹ is O,X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, and Y³ is CR¹. In yet another embodiment, X¹ is O, X² is CR¹R²,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is CR¹.In another embodiment, X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R²,Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² is C. In yet another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)—. In another embodiment, X¹ isO, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹,Y⁴ is CR¹, Y² is C, L is —C(O)—, and R¹ is H. In yet another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is CR¹, Y² is C, L is —C(O)—, R¹ is H, and R^(2′) is aryl orheteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O, wherein the aryl or heteroaryl isoptionally substituted with one or more substituents selected fromhalogen or —R³.

In some embodiments of Formula (I), X¹ is O. In another embodiment, X¹is O and X² is CR¹R². In yet another embodiment, X¹ is O, X² is CR¹R²,and X³ is CR^(1′)R^(2′). In another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), and X⁴ is CR¹R². In yet another embodiment, X¹ is O,X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, and Y³ is CR¹. In yet another embodiment, X¹ is O, X² is CR¹R²,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is CR¹.In another embodiment, X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R²,Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² is C. In yet another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is CR¹, Y² is C, and L is a bond. In another embodiment, X¹ isO, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹,Y⁴ is CR¹, Y² is C, L is a bond, and R^(1′) is H. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is a bond, R^(1′) is H, andR^(2′) is aryl or heteroaryl containing 1 to 5 heteroatoms selected fromthe group consisting of N, S, P, and O, wherein the aryl or heteroarylis optionally substituted with one or more substituents selected fromhalogen or —R³.

In some embodiments of Formula (I), X¹ is O. In another embodiment, X¹is O and X² is CR¹R². In yet another embodiment, X¹ is O, X² is CR¹R²,and X³ is CR^(1′)R^(2′.) In another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), and X⁴ is CR¹R². In yet another embodiment, X¹ is O,X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′,) X⁴ is CR¹R², Y¹is CR¹, and Y³ is CR¹. In yet another embodiment, X¹ is O, X² is CR¹R²,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is CR¹.In another embodiment, X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R²,Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² is C. In yet another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is CR¹, Y² is C, and L is —(CR¹R²)_(n)—. In another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is CR¹, Y² is C, L is —(CR¹R²)_(n)—, and n is 1. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —(CR¹R²)_(n)—, n is 1, andR¹ is H. In yet another embodiment, X¹ is O, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, Lis —(CR¹R²)_(n)—, n is 1, R¹ is H, and R^(2′) is aryl or heteroarylcontaining 1 to 5 heteroatoms selected from the group consisting of N,S, P, and O, wherein the aryl or heteroaryl is optionally substitutedwith one or more substituents selected from halogen or —R³.

In some embodiments of Formula (I), X¹ is O. In another embodiment, X¹is O and X² is CR¹R². In yet another embodiment, X¹ is O, X² is CR¹R²,and X³ is CR^(1′)R^(2′). In another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), and X⁴ is CR¹R². In yet another embodiment, X¹ is O,X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, and Y³ is CR¹. In yet another embodiment, X¹ is O, X² is CR¹R²,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is CR¹.In another embodiment, X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R²,Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² is C. In yet another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)NR³—. In another embodiment, X¹is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is CR¹, Y² is C, L is —C(O)NR³—, and R^(1′) is H. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, L is —C(O)NR³—, R^(1′) is H, andR^(2′) is aryl or heteroaryl containing 1 to 5 heteroatoms selected fromthe group consisting of N, S, P, and O, wherein the aryl or heteroarylis optionally substituted with one or more substituents selected fromhalogen or —R³.

In some embodiments of Formula (I), R is —C₁-C₆ alkyl, —C₄-C₈cycloalkenyl, —C₃-C₈ cycloalkyl, —C₅-C₁₂ spirocycle, heterocyclyl,spiroheterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatomsselected from the group consisting of N, S, P, and O, wherein eachalkyl, cycloalkenyl, cycloalkyl, spirocycle, heterocyclyl,spiroheterocyclyl, aryl, or heteroaryl is optionally substituted withone or more —OH, halogen, oxo, —NO₂, —CN, —R¹, —R², —OR³, —NHR³, —NR³R⁴,—S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, or —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹,—S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl, or heteroaryl containing 1 to5 heteroatoms selected from the group consisting of N, S, P, and O.

In some embodiments of Formula (I), R¹ and R² combine with the atom towhich they are both attached to form a spirocycle. In anotherembodiment, R¹ and R² combine with the atom to which they are bothattached to form a spiroheterocycle. In another embodiment, R¹ and R²combine with the atom to which they are both attached to form aspirocycloalkenyl.

In some embodiments of Formula (I), R¹ and R², when on adjacent atoms,combine to form a heterocycle. In another embodiment, R¹ and R², when onadjacent atoms, combine to form a cycloalkyl. In yet another embodiment,R¹ and R², when on adjacent atoms, combine to form a cycloalkenyl. Inanother embodiment, R¹ and R², when on adjacent atoms, combine to forman aryl. In yet another embodiment, R¹ and R², when on adjacent atoms,combine to form a heteroaryl containing 1 to 5 heteroatoms selected fromthe group consisting of N, S, P, and O.

In some embodiments of Formula (I), R¹ and R², when on non-adjacentatoms, combine to form a bridging cycloalkyl. In another embodiment, R¹and R², when on non-adjacent atoms, combine to form a bridgingcycloalkenyl. In yet another embodiment, R¹ and R², when on non-adjacentatoms, combine to form a heterocycloalkyl.

In some embodiments of Formula (I), R³ and R combine with the nitrogenatom to which they are attached to form a heterocycle optionallysubstituted with —R⁴, —OR⁴, or —NR⁴R⁵. In some embodiments of Formula(I), R³ and R combine with the nitrogen atom to which they are attachedto form a heteroaryl containing 1 to 5 heteroatoms selected from thegroup consisting of N, S, P, and O, optionally substituted with —R⁴,—OR⁴, or —NR⁴R⁵.

In some embodiments of Formula (I), n is 1 to 6. In another embodiment,n is 0 to 5. In yet another embodiment, n is 0 to 4. In yet anotherembodiment, n is 1 to 4. In another embodiment, n is 0 to 3. In yetanother embodiment, n is 0 to 2. In yet another embodiment, n is 0 or 1.In another embodiment, n is 1 or 2.

In some embodiments of Formula (I), X⁴, X², and X¹ are not allsimultaneously CR¹R².

In some embodiments of Formula (I), X¹ is O, X² is CR¹R², and X⁴ isCR¹R². In another embodiment, X² is C═O, X⁴ is C═O, and X¹ is CR¹R². Inyet another embodiment, X¹ is NR³, X² is C═O, and X⁴ is CR¹R².

Non-limiting illustrative compounds of the disclosure include:

-   (S)—N-hydroxy-4-methyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-methyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methoxybenzyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(4-methoxybenzyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3,4-diphenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3,4-diphenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methoxypiperidine-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methylpiperazine-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(4-acetylpiperazine-1-carbonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-phenyl-4-(pyrrolidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N4-cyclohexyl-N8-hydroxy-3-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-3-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-N4,3-diphenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-3-phenyl-N4-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-3-phenyl-N4-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N8-hydroxy-N4,N4-dimethyl-3-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)-4-((4-fluorophenyl)sulfonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(4-chlorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(3-chlorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(4-fluorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;

In another embodiment, non-limiting illustrative compounds of thedisclosure include:

-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(3-fluorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide-   (R)-3-(3-fluorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(2-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-(2-fluorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)-3-(2-fluorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(quinoxalin-6-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(quinolin-6-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(quinolin-7-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(naphthalen-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(quinoxalin-6-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(quinolin-6-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(quinolin-7-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(naphthalen-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(quinoxalin-5-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(quinolin-5-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(quinolin-8-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(naphthalen-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3    S)—N-hydroxy-5-methyl-4-(morpholine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;    and-   (S)-6-fluoro-N-hydroxy-4-(morpholine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide.

In another embodiment of the invention, the compounds of Formula I areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In yet otherembodiments, the compounds of Formula I may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Methods of Synthesizing the Disclosed Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the schemes given below.

The compounds of Formula I may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes and examples. In the schemes described below, it is wellunderstood that protecting groups for sensitive or reactive groups areemployed where necessary in accordance with general principles orchemistry. Protecting groups are manipulated according to standardmethods of organic synthesis (T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection processes, as well as the reaction conditions andorder of their execution, shall be consistent with the preparation ofcompounds of Formula I.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula I. Accordingly, the present invention includes bothpossible stereoisomers (unless specified in the synthesis) and includesnot only racemic compounds but the individual enantiomers and/ordiastereomers as well. When a compound is desired as a single enantiomeror diastereomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be affected by any suitable method known in the art. See, forexample, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. These methods include, but arenot limited, to those methods described below. Compounds of the presentdisclosure can be synthesized by following the steps outlined in GeneralSchemes 1, 2, 3, 4, and 5 which comprise different sequences ofassembling intermediates 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2m,2n, 2o, 2p, 2q, 2r, 2s, 2t, 2u, 2v, 2w, 2x, 2y, 2z, 2aa, 2bb, and 2cc.Starting materials are either commercially available or made by knownprocedures in the reported literature or as illustrated.

wherein L, R, R¹, R²,R^(1′), R^(2′), Y¹ and Y² are defined as in Formula(I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2a, 2b, 2c, 2d, and 2e is outlined in General Scheme 1.Nucleophilic addition of alcohol 2b to Intermediate 2a using a base,e.g., potassium carbonate (K₂CO₃), in a solvent, e.g., acetonitrile(MeCN), provides Intermediate 2c. Cyclization of Intermediate 2c in thepresence of a catalytic amount of a metal catalyst, e.g., copper iodide(CuI), palladium acetate (Pd(OAc)₂), etc., and a base, e.g., potassiumcarbonate (K₂CO₃), in a solvent, e.g., isopropanol (i-PrOH), optionallyat elevated temperature provides Intermediate 2d. Addition of the R-Lmoiety can be achieved via alkylation, reductive amination, arylation,urea formation, or sulfonation. For example, alkylation of Intermediate2d with an alkyl halide in the presence of a base, e.g., sodium hydride(NaH), and optionally at elevated temperatures provides Intermediate 2e.Treatment of Intermediate 2e with hydroxylamine and a base, e.g.,aqueous sodium hydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran(THF) and/or methanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′)are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2f, 2g, 2h, 2i, 2j, and 2k is outlined in General Scheme2. Nucleophilic addition of amine 2g to Intermediate 2f using a base,e.g., N,N-diisopropylethylamine (DIEA), and in a solvent, e.g., MeCN,dichloromethane (DCM), or DMF, provides Intermediate 2h. Protection ofthe amine group in intermediate 2h with a typical acid labile protectinggroup (e.g., t-butoxycarbonyl (Boc)) using an alkyl chloride and4-Dimethylaminopyridine (DMAP), in a solvent e.g., DCM ortetrahydrofuran (THF), followed by hydrogenation in the presence of ametal catalyst, e.g., palladium on carbon, and hydrogen (H₂) gas in asolvent, e.g., DCM, provides Intermediate 2i. Cyclization ofIntermediate 2i in the presence of a base, e.g., potassium carbonate(K₂CO₃), and in a solvent, e.g., isopropanol (i-PrOH), optionally atelevated temperatures provides Intermediate 2j. Addition of the R-Lmoiety can be achieved via alkylation, reductive amination, arylation,urea formation, or sulfonation. For example, alkylation of Intermediate2j with an alkyl halide in the presence of a base, e.g., sodium hydride(NaH), and optionally at elevated temperatures provides Intermediate 2k.Treatment of Intermediate 2k with hydroxylamine and a base, e.g.,aqueous sodium hydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran(THF) and/or methanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′)are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2m, 2n, 2o, 2p, and 2q, is outlined in General Scheme 3.Sulfonylation of alcohol 2n with Intermediate 2m in the presence of ametal oxide, e.g., MgO, and in a solvent, e.g., THF and or water (H₂O),provides Intermediate 2o. Cyclization of Intermediate 2o in the presenceof a base, e.g., sodium methoxide (NaOMe), and in a solvent, e.g.,methanol (MeOH), i-PrOH, etc., provides Intermediate 2p. Addition of theR-L moiety can be achieved via alkylation, reductive amination,arylation, urea formation, or sulfonation. For example, alkylation ofIntermediate 2p with an alkyl halide in the presence of a base, e.g.,sodium hydride (NaH), and optionally at elevated temperatures providesIntermediate 2q. Treatment of Intermediate 2q with hydroxylamine and abase, e.g., aqueous sodium hydroxide (aq. NaOH), in a solvent, e.g.,tetrahydrofuran (THF) and/or methanol (MeOH), provides compounds ofFormula (I).

wherein L, R, R^(1′), and R^(2′)are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2r, 2s, 2t, 2u, and 2v, is outlined in General Scheme 4.Intermediate 2t can be obtained by alkylation of 2s with phenol 2r usinga Mitsunobu reagent (e.g., diethyl azodicarboxylate (DEAD) ordiisopropyl azodicarboxylate (DIAD)), and triphenyl phosphine in asolvent, e.g., tetrahydrofuran (THF), dichloromethane (DCM).Deprotection of intermediate 2t using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM),followed by cyclization in the presence of a base, e.g., triethylamine(Et₃N), and optionally in a solvent, e.g., THF, MeOH, etc., at elevatedtemperature provides Intermediate 2u. Addition of the R-L moiety can beachieved via alkylation, reductive amination, arylation, urea formation,or sulfonation. For example, alkylation of Intermediate 2u with an alkylhalide in the presence of a base, e.g., sodium hydride (NaH), andoptionally at elevated temperatures provides Intermediate 2v. Treatmentof Intermediate 2v with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran (THF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′)are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2w, 2x, 2y, 2z, 2aa, 2bb, and 2cc, is outlined in GeneralScheme 5. Alkylation of phenol 2w with Intermediate 2x using potassiumiodide (KI) and a base, e.g., potassium carbonate (K₂CO₃), in a solvent,e.g., MeCN, THF, etc., provides Intermediate 2y. Deprotection ofIntermediate 2y using a strong acid such as trifluoroacetic acid (TFA)in a solvent, e.g., dichloromethane (DCM) followed by cyclization viaintramolecular reductive amination in the presence of sodium borohydrideor sodium cyanoborohydride in a solvent, e.g., THF, MeOH, etc., providesIntermediate 2z. Protection of the amine group in intermediate 2z with atypical acid labile protecting group (e.g., t-butoxycarbonyl (Boc))using an alkyl chloride and optionally 4-DMAP in a solvent e.g., DCM ortetrahydrofuran (THF), followed by carbonylation in the presence of ametal catalyst, e.g.,[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, andcarbon monoxide (CO) gas in a solvent, e.g., DCM, provides Intermediate2aa. Deprotection of intermediate 2aa using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM)provides Intermediate 2bb. Addition of the R-L moiety can be achievedvia alkylation, reductive amination, arylation, urea formation, orsulfonation. For example, alkylation of Intermediate 2bb with an alkylhalide in the presence of a base, e.g., sodium hydride (NaH), andoptionally at elevated temperatures provides Intermediate 2cc. Treatmentof Intermediate 2cc with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH), in a solvent, e.g., tetrahydrofuran (THF) and/ormethanol (MeOH), provides compounds of Formula (I).

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating adisease associated with HDAC, e.g., HDAC6, modulation in a subject inneed thereof. The method involves administering to a patient in need oftreatment for diseases or disorders associated with HDAC, e.g., HDAC6,modulation an effective amount of a compound of Formula I. In anembodiment, the disease can be, but is not limited to, cancer,neurodegenerative disease, neurodevelopmental disease, inflammatory orautoimmune disease, infection, metabolic disease, hematologic disease,or cardiovascular disease.

Another aspect of the invention is directed to a method of inhibiting anHDAC, e.g., HDAC6. The method involves administering to a patient inneed thereof an effective amount of Formula I.

The present invention relates to compositions capable of modulating theactivity of (e.g., inhibiting) HDACs, for instance HDAC6. The presentinvention also relates to the therapeutic use of such compounds.

One therapeutic use of the compounds of the present invention is totreat proliferative diseases or disorders such as cancer. Cancer can beunderstood as abnormal or unregulated cell growth within a patient andcan include, but is not limited to lung cancer, ovarian cancer, breastcancer, prostate cancer, pancreatic cancer, hepatocellular cancer, renalcancer and leukemias such as acute myeloid leukemia and acutelymphoblastic leukemia. Additional cancer types include T-cell lymphoma(e.g., cutaneous T-cell lymphoma, peripheral T-cell lymphoma), andmultiple myeloma.

One therapeutic use of the compounds of the present invention is totreat neurological diseases or disorders or neurodegeneration.Neurological disorders are understood as disorders of the nervous system(e.g., the brain and spinal cord). Neurological disorders orneurodegenerative diseases can include, but are not limited to epilepsy,attention deficit disorder (ADD), Alzheimer's disease, Parkinson'sDisease, Huntington's Disease, amyotrophic lateral sclerosis, spinalmuscular atrophy, essential tremor, central nervous system trauma causedby tissue injury, oxidative stress-induced neuronal or axomaldegeneration, and multiple sclerosis.

Another therapeutic use of the compounds of the present invention is totreat neurodevelopmental disorders. Neurodevelopmental disorders caninclude, but are not limited to, Rett syndrome.

Another therapeutic use of the compounds of the present invention isalso to treat inflammatory diseases or disorders. Inflammation can beunderstood as a host's response to an initial injury or infection.Symptoms of inflammation can include, but are not limited to redness,swelling, pain, heat and loss of function. Inflammation may be caused bythe upregulation of pro-inflammatory cytokines such as IL-1β, andincreased expression of the FOXP3 transcription factor.

Another therapeutic use of the compounds of the present invention isalso to treat autoimmune diseases or disorders. Autoimmune disorders areunderstood as disorders wherein a host's own immune system responds totissues and substances occurring naturally in the host's body.Autoimmune diseases can include, but are not limited to Rheumatoidarthritis, spondylitis arthritis, psoriatic arthritis, multiplesclerosis, systemic lupus erythematosus, inflammatory bowel disease,graft versus host disease, transplant rejection, fibrotic disease,Crohn's Disease, type-1 diabetes, Eczema, and psoriasis.

Another therapeutic use of the compounds of the present invention isalso to treat infectious diseases or disorders. Infections or infectiousdiseases are caused by the invasion of a foreign pathogen. The infectionmay be caused by, for instance, a bacteria, a fungus, or virus. Forexample, a bacterial infection may be caused by a E. coli.

Yet another therapeutic use of the compounds of the present invention isalso to treat metabolic diseases or disorders. Metabolic diseases can becharacterized as abnormalities in the way that a subject stores energy.Metabolic disorders can include, but are not limited to metabolicsyndrome, diabetes, obesity, high blood pressure, and heart failure.

Yet another therapeutic use of the compounds of the present invention isalso to treat hematologic disorders. Hematologic diseases primarilyaffect the blood. Hematologic disorders can include, but are not limitedto anemia, lymphoma, and leukemia.

Yet another therapeutic use of the compounds of the present invention isalso to treat cardiovascular diseases or disorders. Cardiovasculardiseases affect the heart and blood vessels of a patient. Exemplaryconditions include but are not limited to cardiovascular stress,pressure overload, chronic ischemia, infarction-reperfusion injury,hypertension, atherosclerosis, peripheral artery disease, and heartfailure.

Another aspect of the present disclosure relates to a compound ofFormula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in treating orpreventing a disease associated with HDAC6 modulation. In someembodiments, the disease is cancer, neurodegenerative disease,neurodevelopmental disorder, inflammatory or autoimmune disease,infection, metabolic disease, hematologic disease, or cardiovasculardisease. In some embodiments, the compound inhibits a histonedeacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In another aspect, the present disclosure relates to the use of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the manufactureof a medicament for treating or preventing a disease associated withHDAC6 modulation. In some embodiments, the disease is cancer,neurodegenerative disease, neurodevelopmental disorder, inflammatory orautoimmune disease, infection, metabolic disease, hematologic disease,or cardiovascular disease. In some embodiments, the compound inhibits ahistone deacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In some embodiments, the cancer is cutaneous T-cell lymphoma, peripheralT-cell lymphoma, multiple myeloma, leukemia, lung, ovarian, breast,prostate, pancreatic, hepatocellular or renal cancer. In otherembodiments, the neurodegenerative disease is Alzheimer's, Huntington's,Parkinson's, Amyotrophic Lateral Sclerosis, or spinal muscular atrophy.In other embodiments, the neurodevelopmental disorder is Rett syndrome.In yet other embodiments, the inflammatory or autoimmune disease isrheumatoid arthritis, spondylitis arthritis, psoriatic arthritis,psoriasis, multiple sclerosis, systemic lupus erythematosus,inflammatory bowel diseases, graft versus host disease, transplantrejection or fibrotic disease.

The disclosed compound can be administered in effective amounts to treator prevent a disorder and/or prevent the development thereof insubjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, all using forms well known to thoseskilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, alginic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can include,polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspanamidephenol,or polyethyleneoxidepolylysine substituted with palmitoyl residues.Furthermore, the disclosed compounds can be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacrylates and cross-linked or amphipathic block copolymers ofhydrogels. In one embodiment, disclosed compounds are not covalentlybound to a polymer, e.g., a polycarboxylic acid polymer, or apolyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of Formula I and a pharmaceutically acceptablecarrier. The pharmaceutically acceptable carrier can further include anexcipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

Without wishing to be bound by any particular theory, the compounds ofthe present invention can inhibit HDACs such as HDAC6 by interactingwith the zinc (Zn²⁺) ion in the protein's active site via the hydroxamicacid group bound to the aromatic ring of the compound. The binding canprevent the zinc ion from interacting with its natural substrates, thusinhibiting the enzyme.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis examples, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

The present invention includes a number of unique features andadvantages compared with other inhibitors of HDAC enzymes, in particularHDAC6. For instance, the present invention features a unique class ofsmall molecule therapeutic agents of Formula I. The compounds weredesigned by using crystal structure information of HDAC ligand-proteincomplexes as well as advanced computational chemistry tools. Thesetechniques led to the development of new chemical scaffolds that wereiteratively refined to optimize key recognition features between theligand and receptor known to be necessary for potency.

Definitions used in the following examples and elsewhere herein are:

aq.: aqueous

Boc t-butoxycarbonyl

CDCl₃: deuterated chloroform

CH₂Cl₂: methylene chloride, dichloromethane

Cu(OAc)₂ copper (II) acetate

CuI: copper (I) iodide

DMSO: dimethylsulfoxide

Et₃N: triethylamine

EtOAc: ethyl acetate

h: hours

H₂O: water

HCl: hydrochloric acid

K₂CO₃: potassium carbonate

MeCN: acetonitrile

MeOH: methanol

MgSO₄: magnesium sulfate

min: minutes

NaBH(OAc)₃ sodium triacetoxyborohydride

Na₂SO₄: sodium sulfate

NaOH: sodium hydroxide

NH₂OH: hydroxylamine

NH₄HCO₃: ammonium bicarbonate

NH₄OH ammonium hydroxide

pet. ether: petroleum ether

prep-HPLC: preparatory high pressure liquid chromatography

TFA: trifluoroacetic acid

THF: tetrahydrofuran

Example 1—Preparation of(S)—N-hydroxy-4-methyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((2-hydroxy-1-phenylethyl)amino)methyl)benzoate

(S)-2-Amino-2-phenylethan-1-ol (7.5 g, 54.67 mmol, 2 equiv) and K₂CO₃(5.68 g, 40.8 mmol, 1.5 equiv) in MeCN (120 mL) were added to a 500-mLround-bottom flask. This was followed by the dropwise addition of asolution of methyl 3-bromo-4-(bromomethyl)benzoate (14 g, 45.46 mmol, 1equiv) in MeCN (130 mL) with stirring at 0° C. The resulting mixture wasstirred overnight at room temperature. The solids were removed byfiltration, and the filtrate was concentrated under vacuum. The residuewas purified by silica gel chromatography (EtOAc/pet. ether, 1:1) toafford the title compound as a yellow oil (9 g, 54% yield). MS: (ES,m/z): 364 [M+H]⁺.

Step-2: Methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A solution of methyl(S)-3-bromo-4-(((2-hydroxy-1-phenylethyl)amino)methyl) benzoate (5 g,13.73 mmol, 1 equiv) in isopropanol (120 mL) was added to a 150-mLsealed tube purged and maintained with an inert atmosphere of nitrogen.This was followed by the addition of K₂CO₃ (2.85 g, 20.47 mmol, 1.5equiv) and CuI (0.78 g, 4.12 mmol, 0.3 equiv). The resulting mixture wasstirred overnight at 110° C. in an oil bath. The reaction was cooled toroom temperature and then concentrated under vacuum. The residue wasdiluted with water (200 mL) and extracted with EtOAc (2×100 mL). Thecombined organic layers were washed with a 30% NH₄OH solution (100 mL)and brine (200 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:3 to 1:1) to afford the titlecompound as a yellow solid (1.4 g, 36% yield). MS: (ES, m/z): 284[M+H]⁺.

Step-3: Methyl(S)-4-methyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (150mg, 0.53 mmol, 1 equiv), acetic acid (4.5 mL), and acetal (116 mg, 2.65mmol, 5 equiv) were added to a 25-mL round-bottom flask. The resultingmixture was stirred for 2 h at room temperature and NaBH(OAc)₃ (900 mg,4.24 mmol, 8 equiv) was then added. The resulting mixture was stirredovernight at room temperature and then concentrated under vacuum. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:1) to afford the title compound as a colorless oil (100 mg, 63%yield). MS: (ES, m/z): 298 [M+H]⁺.

Step-4:(S)—N-Hydroxy-4-methyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-4-methyl-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.34 mmol, 1 equiv), THF/MeOH (4:1, 1.25 mL), NH₂OH (50% inwater, 2218 mg, 34 mmol, 100 equiv), and aq. 1N NaOH (0.67 mL, 2 equiv)were added to a 25-mL round-bottom flask and the resulting solution wasstirred for 3 h at room temperature. The crude product was purified byPrep-HPLC (Column: XBridge C18, 5 μm, 19×150 mm; Mobile Phase A:Water/0.1% formic acid; Mobile Phase B: MeCN; Detector: UV 254, 220 nm)to afford the title compound as a white solid (47.3 mg, 42% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.80-11.37 (m, 2H), 9.27-9.02 (m,1H), 7.65-7.38 (m, 8H), 4.96-4.28 (m, 5H), 2.69 (s, 2H), 2.33 (s, 1H).MS: (ES, m/z): 299 [M+H]⁺.

TABLE 1 The following compounds were prepared according to the method ofExample 1, using (R)-2-amino-2-phenylethan-1-ol or(S)-2-amino-2-phenylethan-1-ol in Step 1 where appropriate. FoundStructure M + H ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 299 [M + H]⁺ 11.78-11.31 (m, 2H), 9.21 (br s, 1H), 7.72- 7.38(m, 8H), 5.03-4.93 (m, 1H), 4.86-4.63 (m, 2H), 4.53-4.49 (m, 1H),4.34-4.27 (m, 1H), 2.69 (s, 2H), 2.36 (s, 1H)

(ES, m/z): 405 [M + H]⁺ 11.37-11.00 (m, 2H), 7.72-6.92 (m, 12H), 4.98(s, 1H), 4.63-4.36 (m, 3H), 4.26 (m, 2H), 3.87-3.36 (m, 4H)

(ES, m/z): 405 [M + H]⁺ 11.48-11.10 (m, 2H), 7.71-6.89 (m, 12H),4.97-4.00 (m, 6H), 3.86-3.33 (m, 4H)

Example 2—Preparation of(S)—N-hydroxy-3,4-diphenyl-2,3,4,5-tetrahydrobenzoI[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3,4-diphenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.35 mmol, 1 equiv), CH₂Cl₂ (5 mL), phenylboronic acid (129 mg, 1.06mmol, 3 equiv), and 4 Å molecular sieves (35.3 mg, 100 mg/mmol) wereadded to a 25-mL round-bottom flask and the resulting mixture wasstirred for 5 min at room temperature. Cu(OAc)₂ (64 mg, 0.35 mmol, 1equiv) and Et₃N (107.1 mg, 1.06 mmol, 3 equiv) were then added andoxygen gas was introduced into the reaction. The resulting mixture wasstirred for an additional 2 days at room temperature and thenconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:10) to afford the title compound asa colorless oil (35.2 mg, 28% yield). MS: (ES, m/z): 360 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3,4-diphenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3,4-diphenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(35.2 mg, 0.10 mmol, 1 equiv), THF/MeOH (4:1, 1.25 mL), NH₂OH (50% inwater, 1574 mg, 10 mmol, 100 equiv), and aq. 1N NaOH (0.38 mL, 4 equiv)were added to a 25-mL round-bottom flask and the resulting solution wasstirred for 4 h at room temperature. The crude product was purified byprep-HPLC (Column: XBridge C18, 5 μm, 19×150 mm; Mobile Phase A:Water/0.1% formic acid; Mobile Phase B: MeCN; Detector: UV 254, 220 nm)to afford the title compound as a yellow solid (3 mg, 8% yield). ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 11.22-11.09 (m, 1H), 7.60-7.34 (m, 7H), 7.17(s, 1H), 7.08-7.04 (m, 2H), 6.60-6.56 (m, 3H), 5.30-5.20 (m, 2H),4.81-4.59 (m, 3H). MS: (ES, m/z): 361 [M+H]⁺.

TABLE 2 The following compound was prepared according to the method ofExample 2, using (R)-2-amino-2-phenylethan-1-ol or(S)-2-amino-2-phenylethan-1-ol in Step 1. Found Structure M + H ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 361 [M + H]⁺ 11.15 (br s, 1H), 7.54-7.31 (m, 7H), 7.16- 7.13(m, 1H), 7.08-6.55 (m, 5H), 5.29-5.20 (m, 2H), 4.81-4.67 (m, 3H)

Example 3—Preparation of(S)—N-hydroxy-4-(4-methoxypiperidine-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzoI[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(4-methoxypiperidine-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (50mg, 0.18 mmol, 1 equiv), THF (8 mL), triphosgene (17 mg, 0.07 mmol, 0.33equiv), and Et₃N (36 mg, 0.36 mmol, 2 equiv) were added to a 25-mLround-bottom flask and the resulting mixture was stirred for 30 min atroom temperature. This was followed by the dropwise addition of asolution of 4-methoxypiperidine (22 mg, 0.19 mmol, 1.1 equiv) in THF (2mL) with stirring and the resulting solution was stirred for 30 min atroom temperature. The reaction mixture was then poured into 20 mL ofwater and extracted with CH₂Cl₂ (2×50 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered, and concentrated undervacuum to afford the title compound as a brown oil (60 mg, 80% yield).MS: (ES, m/z): 425 [M+H]⁺.

Step-2:(S)—N-Hydroxy-4-(4-methoxypiperidine-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-4-(4-methoxypiperidine-1-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(60 mg, 0.14 mmol, 1 equiv) and THF/MeOH (4:1, 2 mL) were added to a25-mL round-bottom flask. This was followed by the dropwise addition ofa solution of aq. 1N NaOH (11 mg, 0.28 mmol, 2 equiv) dissolved in theNH₂OH (50% in water, 560 mg, 8.49 mmol, 60 equiv) with stirring at 0° C.and the resulting solution was stirred for 3 h at room temperature. Thesolids were then removed by filtration and the crude product waspurified by prep-HPLC (Column: XBridge C18 OBD, 5 μm, 19×250 mm; MobilePhase A: Water/0.1% formic acid; Mobile Phase B: MeCN; Gradient: hold at30% B for 8 min; Detector: UV 254, 220 nm) to afford the title compoundas an off-white solid (31.9 mg, 27% yield). ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 11.15 (br s, 1H), 9.02 (br s, 1H), 7.42-7.20 (m, 8H), 5.22-5.18(m, 1H), 4.72-4.57 (m, 3H), 4.41-4.36 (m, 1H), 3.28-3.19 (m, 6H),2.79-2.71 (m, 2H), 1.78-1.66 (m, 2H), 1.37-1.28 (m, 2H). MS: (ES, m/z):426 [M+H]⁺.

TABLE 3 The following compounds were prepared according to the method ofExample 3. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 411 [M + H]⁺ 11.20 (br s, 1H), 10.92 (m, 1H), 7.43-7.23 (m,7H), 7.22 (s, 1H), 5.32-5.29 (m, 1H), 4.78 (d, J = 16.4 Hz, 1H), 4.66(d, J = 16.8 Hz, 1H), 4.60-4.56 (m, 1H), 4.50-4.45 (m, 1H), 3.51-3.38(m, 2H), 3.31-3.15 (m, 2H), 3.12-2.93 (m, 4H), 2.71 (s, 3H)

(ES, m/z): 439 [M + H]⁺ 11.11 (br s, 1H), 9.04 (br s, 1H), 7.43-7.36 (m,4H), 7.34-7.28 (m, 3H), 7.21 (s, 1H), 5.29-5.28 (m, 1H), 4.78-4.65 (m,2H), 4.62-4.58 (m, 1H), 4.45-4.40 (m, 1H), 3.44-3.37 (m, 2H), 3.34-3.29(m, 2H), 3.00-2.93 (m, 4H), 1.95 (s, 3H)

(ES, m/z): 396 [M + H]⁺ 11.13 (br s, 1H), 9.03 (br s, 1H), 7.40-7.39 (m,4H), 7.34-7.26 (m, 3H), 7.20-7.19 (m, 1H), 5.20-5.17 (m, 1H), 4.71-4.58(m, 3H), 4.41-4.35 (m, 1H), 2.96-2.95 (m, 4H), 1.46-1.35 (m, 6H)

(ES, m/z): 382 [M + H]⁺ 7.22-7.47 (m, 8H), 5.44-5.40 (m, 1H), 4.84-4.83(m, 2H), 4.79-4.64 (m, 1H), 4.45-4.39 (m, 1H), 3.35 (s, 1H), 3.30-3.26(m, 1H), 3.20-3.15 (m, 2H), 1.83-1.80 (m, 4H)

(ES, m/z): 410 [M + H]⁺ 11.16 (br s, 1H), 9.03 (br s, 1H), 7.41-7.28 (m,7H), 7.21 (s, 1H), 5.99 (d, J = 8.0 Hz, 1H), 5.69-5.67 (m, 1H),4.94-4.90 (m, 1H), 4.66-4.50 (m, 3H), 1.71-1.61 (m, 2H), 1.51-1.43 (m,3H), 1.19-1.04 (m, 5H)

(ES, m/z): 412 [M + H]⁺ 11.21 (br s, 1H), 9.02 (br s, 1H), 7.41-7.22 (m,8H), 6.17 (d, J = 7.6 Hz, 1H), 5.70- 5.67 (m, 1H), 4.93 (d, J = 16.8 Hz,1H), 4.67-4.51 (m, 3H), 3.78-3.55 (m, 3H), 3.28-3.18 (m, 2H), 1.67-1.64(m, 1H), 1.44-1.39 (m, 2H), 1.29-1.25 (m, 1H)

(ES, m/z): 404 [M + H]⁺ 8.44 (s, 1H), 7.44-7.30 (m, 9H), 7.25 (s, 1H),7.24-7.17 (m, 2H), 6.94-6.90 (m, 1H), 5.91-5.87 (m, 1H), 5.14 (d, J =17.2 Hz, 1H), 4.80-4.61 (m, 3H)

(ES, m/z): 405 [M + H]⁺ 11.16 (br s, 1H), 9.04-9.02 (m, 1H), 8.92 (s,1H), 8.23 (d, J = 6.4 Hz, 2H), 7.45-7.40 (m, 6H), 7.34-7.31 (m, 3H),7.24 (s, 1H), 5.91-5.88 (m, 1H), 5.17-5.13 (m, 1H), 4.81-4.65 (m, 3H)

(ES, m/z): 405 [M + H]⁺ 11.07 (s, 1H), 9.03 (s, 1H), 8.71 (s, 1H), 8.56(d, J = 2.4 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.82 (d, J = 0.8 Hz, 1H),7.45- 7.29 (m, 7H), 7.28-7.20 (m, 2H), 5.89-5.86 (m, 1H), 5.13 (d, J =17.2 Hz, 1H), 4.85- 4.62 (m, 3H)

Example 4—Preparation of(S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(morpholine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A solution of methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.35 mmol, 1 equiv) in CH₂Cl₂ (6 mL) was added to a 40-mL vialfollowed by addition of morpholine-4-carbonyl chloride (80 mg, 0.53mmol, 1.5 equiv), Et₃N (140 mg, 1.38 mmol, 4 equiv), and4-dimethylaminopyridine (403 mg, 3.30 mmol, 0.1 equiv) at roomtemperature. The resulting solution was stirred for 8 h at 50° C. Thereaction mixture was diluted with CH₂Cl₂ (30 mL) and was washed withbrine (3×20 mL). The combined organic layers were dried over anhydrousNa₂SO₄, filtered, and concentrated under vacuum to afford the titlecompound as a white solid (70 mg, 50% yield). MS: (ES, m/z): 397 [M+H]⁺.

Step-2:(S)—N-Hydroxy-4-(morpholine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

A solution of methyl(S)-4-(morpholine-4-carbonyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(70 mg, 0.18 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL) was added to an 8-mLvial followed by the addition of aq. 1N NaOH (0.4 mL, 2 equiv), andNH₂OH (50% in water, 1.6 mL, 120 equiv). The resulting solution wasstirred for 1 h at room temperature and the crude product was purifiedby prep-HPLC (Column: XBridge C18 OBD, 5 μm, 19×250 mm; Mobile Phase A:Water/0.1% formic acid; Mobile Phase B: MeCN; Gradient: 5% B to 49% B in8 min; Flow rate: 20 mL/min; Detector: UV 254, 220 nm) to afford thetitle compound as light yellow solid (42.8 mg, 61% yield). ¹H-NMR (300MHz, DMSO-d₆) δ(ppm): 11.12 (s, 1H), 9.01 (s, 1H), 7.12-7.41 (m, 8H),5.23-5.27 (m, 1H), 4.56-4.73 (m, 4H), 4.37-4.42 (m, 4H), 3.31-3.55 (s,4H). MS: (ES, m/z): 398 [M+H]⁺.

Example 5—Preparation of(S)—N8-hydroxy-N4,N4-dimethyl-3-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

A 2-mL reaction vial was charged with methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(0.2M in 1,2-dichloroethane, 200 μL, 40 μmol) and Et₃N (neat, 11 μL, 80μmol). Dimethylcarbamic chloride (0.2M in 1,2-dichloroethane, 400 μL, 80μmol) was then added and the vial was sealed and shaken at roomtemperature overnight. The reaction mixture was diluted with brine (500μL) and extracted with EtOAc (2×500 μL). The combined organic layerswere evaporated to dryness under reduced pressure. THF/MeOH (3:1, 180μL) was added to the vial of methyl(S)-4-(dimethylcarbamoyl)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduced pressure and the residue was dissolved inDMSO (500 μL) and purified by HPLC to afford the title compound (6.9 mg,48.5% yield). MS: (ES, m/z): 356 [M+H]⁺.

Example 6—Preparation of(S)-4-((4-fluorophenyl)sulfonyl)-N-hydroxy-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (0.2M in 1,2-dichloroethane, 150 μL, 30 μmol) and Et₃N (neat, 10 μL, 71μmol) were added to a 2-mL reaction vial followed by4-Fluorobenzenesulfonyl chloride (0.2 M in 1,2-dichloroethane, 195 μL,39 μmol). The vial was then sealed and shaken at room temperatureovernight. The reaction mixture was diluted with brine (500 μL) andextracted with EtOAc (2×500 μL). The combined organic layers wereevaporated to dryness under reduced pressure. THF/MeOH (3:1, 180 μL) wasadded to the vial containing methyl4-((4-fluorophenyl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was then added followed by aq. 1N NaOH (85 μL)and the vial was sealed and shaken at room temperature overnight. Thesolvent was evaporated under reduced pressure and the residue wasdissolved in DMSO (500 μL) then purified by HPLC to afford the titlecompound. MS: (ES, m/z): 443 [M+H]⁺.

Example 7—Preparation of(S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzoate

A solution of (S)-2-amino-2-(4-(trifluoromethyl)phenyl)ethan-1-ol (670mg, 3.27 mmol, 1 equiv) in MeCN (60 mL) was added to a 250-mLround-bottom flask followed by the portionwise addition of K₂CO₃ (2.25g, 16.28 mmol, 5 equiv). To this mixture was added a solution of methyl3-bromo-4-(bromomethyl)benzoate (1000 mg, 3.25 mmol, 1 equiv) in MeCN(20 mL) dropwise with stirring and the resulting solution was stirredovernight at 50° C. in an oil bath. The reaction mixture was then cooledto room temperature and concentrated under vacuum. The resulting residuewas dissolved in water (50 mL) and extracted with EtOAc (2×80 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:1) to afford the title compound asan orange oil (1.04 g, 74% yield). MS: (ES, m/z): 432 [M+H]⁺.

Step-2: Methyl (S)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzoI[f][1,4]oxazepine-8-carboxylate

A solution of methyl(S)-3-bromo-4-(((2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)benzoate (1.04 g, 2.41 mmol, 1 equiv) in isopropanol (18mL) was added to a 20-mL sealed tube followed by the portionwiseaddition of CuI (230 mg, 1.21 mmol, 0.5 equiv). To this mixture wasadded K₂CO₃ (500 mg, 3.62 mmol, 1.5 equiv), in portions and theresulting solution was stirred overnight at 105° C. in an oil bath. Thereaction mixture was then cooled to room temperature and the solids wereremoved by filtration. The filtrate was concentrated under vacuum. Theresulting residue was dissolved in EtOAc (60 mL) and washed with brine(3×30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered,and concentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:1) to afford the title compound as agreen solid (560 mg, 43% yield). MS: (ES, m/z): 352 [M+H]⁺.

Step-3: Methyl(S)-4-(morpholine-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A solution of methyl(S)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(80 mg, 0.23 mmol, 1 equiv) in CH₂Cl₂ (3 mL) and Et₃N (92 mg, 0.91 mmol,4 equiv) were added to an 8-mL vial followed by the portionwise additionof triphosgene (33.6 mg, 0.11 mmol, 0.5 equiv) at 0° C. The resultingmixture was stirred for 30 min at room temperature and morpholine (40mg, 0.46 mmol, 2.02 equiv) was then added dropwise with stirring. Theresulting solution was stirred for 3 h at room temperature. The reactionmixture was concentrated under vacuum and the resulting residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a light yellow oil (90 mg, 55% yield). MS: (ES,m/z): 465 [M+H]⁺.

Step-4:(S)—N-Hydroxy-4-(morpholine-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

A solution of methyl(S)-4-(morpholine-4-carbonyl)-3-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(90.0 mg, 0.19 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL) was added to an8-mL vial followed by the dropwise addition of aq. 1N NaOH (0.38 mL, 2equiv) with stirring. To this mixture was added NH₂OH (50% in water, 767mg, 11.63 mmol, 60 equiv) dropwise with stirring and the resultingsolution was stirred for 3 h at room temperature. The crude product waspurified by prep-HPLC (Column: Xbridge C18 OBD, 5 μm, 19×150 mm; MobilePhase A: Water/0.1% formic acid; Mobile Phase B: MeCN; Gradient: 5% B to55% B in 7 min; Detector: UV 254, 220 nm) to afford the title compoundas a white solid (30.9 mg, 34% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.14 (br s, 1H), 9.05 (br, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0Hz, 2H), 7.36-7.30 (m, 2H), 7.22 (d, J=1.6 Hz, 1H), 5.33-5.30 (m, 1H),4.72-4.65 (m, 3H), 4.46-4.41 (m, 1H), 3.57-3.47 (m, 4H), 3.04-2.97 (m,4H). MS: (ES, m/z): 466 [M+H]⁺.

Example 8—Preparation of(S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((2-hydroxy-1-(p-tolyl)ethyl)amino)methyl)benzoate

(S)-2-Amino-2-(p-tolyl)ethanol (209 mg, 1.380 mmol, 1 equiv), K₂CO₃ (572mg, 4.14 mmol, 3 equiv), and MeCN (15 mL) were added to a 40-mL vialequipped with a stir bar and the resulting slurry was cooled to 0° C. inan ice-water bath. A solution of methyl 3-bromo-4-(bromomethyl)benzoate(425 mg, 1.380 mmol, 1 equiv) in MeCN (3 mL) was then added dropwiseover 10 min while maintaining the internal temperature at 0° C. The icebath was removed and the resulting slurry was allowed to slowly warm toroom temperature. Stirring was continued at room temperature for 16 hand the reaction was concentrated under reduced pressure to remove mostof the MeCN. The concentrated mixture was partitioned between EtOAc (10mL) and H₂O (5 mL). The phases were separated and the organic phase waswashed with brine (5 mL), dried over Na₂SO₄, filtered, and concentratedto afford the title compound as a pale yellow oil (522 mg). MS: (ES,m/z): 379 [M+H]⁺.

Step-2: Methyl(S)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl (S)-3-bromo-4-(((2-hydroxy-1-(p-tolyl)ethyl)amino)methyl)benzoate(522 mg, 1.380 mmol, 1 equiv) in isopropanol (8 mL) and K₂CO₃ (381 mg,2.76 mmol, 2 equiv) were added to a 40-mL vial equipped with a stir barfollowed by CuI (52.6 mg, 0.276 mmol, 0.2 equiv). The resulting solutionwas heated to reflux for 18 h. The reaction mixture was filtered througha celite pad and washed with isopropanol (10 mL). The filtrate wasreduced in volume to ˜5 mL and 10N HCl (1.1 equiv) was added dropwise,with stirring, to the filtrate. The resulting slurry was cooled in anice bath for 30 min before being filtered on a Buchner funnel to affordthe HCl salt of the title compound as a pale yellow solid (140.4 mg,30.5% yield). MS: (ES, m/z): 298 [M+H]⁺.

Step-3: Methyl(S)-4-(morpholine-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (20 mg, 0.06 mmol, 1 equiv), Et₃N (0.029 mL, 0.21 mmol,3.5 equiv), morpholine-4-carbonyl chloride (10.75 mg, 0.072 mmol, 1.2equiv), and MeCN (2 mL) were added to a 4-mL vial equipped with a stirbar and the resulting solution was stirred at room temperature for 4 h.The reaction was concentrated to dryness to afford the title compound asa colorless oil (27.2 mg). MS: (ES, m/z): 411 [M+H]⁺.

Step-4:(S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-4-(morpholine-4-carbonyl)-3-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(27.2 mg, 0.066 mmol, 1 equiv), NH₂OH (50% in water, 0.087 mL, 1.32mmol, 20 equiv), and aq. 1N NaOH (0.13 mL, 2 equiv) in a solution ofTHF/MeOH (4:1, 1.5 mL) were added to a 4-mL vial and the resultingsolution was stirred at room temperature overnight. The reaction wasconcentrated to dryness and purified by prep-HPLC (Column: Xbridge PrepC18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% formic acid; MobilePhase B: MeCN/0.1% formic acid; Flow rate: 23 mL/min; Gradient: 0% B upto 35% B in 8 min; Detector: UV 254, 220 nm) to afford the titlecompound as a white solid (10.3 mg, 37.8% yield). MS: (ES, m/z): 412[M+H]⁺.

Example 9—Preparation of(S)-3-(4-chlorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-(4-chlorophenyl)-2-hydroxyethyl)amino)methyl)benzoate

(S)-2-Amino-2-(4-chlorophenyl)ethan-1-ol (237 mg, 1.38 mmol, 1 equiv),K₂CO₃ (572 mg, 4.14 mmol, 3 equiv), and MeCN (15 mL) were added to a40-mL vial equipped with a stir bar and the resulting slurry was cooledto 0° C. in an ice-water bath. A solution of methyl3-bromo-4-(bromomethyl)benzoate (425 mg, 1.38 mmol, 1 equiv) in MeCN (3mL) was then added dropwise over 10 min while maintaining the internaltemperature at 0° C. The ice bath was removed and the resulting slurrywas allowed to slowly warm to room temperature. Stirring was continuedat room temperature for 16 h and the reaction was concentrated underreduced pressure to remove most of the MeCN. The concentrated mixturewas partitioned between EtOAc (10 mL) and H₂O (5 mL). The phases wereseparated and the organic phase was washed with brine (5 mL), dried overNa₂SO₄, filtered, and concentrated to afford the title compound as apale yellow oil (572 mg). MS: (ES, m/z): 399 [M+H]⁺.

Step-2: Methyl (S)-3-(4-chlorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-bromo-4-(((1-(4-chlorophenyl)-2-hydroxyethyl)amino)methyl)benzoate(572 mg, 1.435 mmol, 1 equiv) in isopropanol (5 mL) and K₂CO₃ (397 mg,2.87 mmol, 2 equiv) were added to a 40-mL vial equipped with a stir barfollowed by CuI (54.6 mg, 0.287 mmol, 0.2 equiv). The resulting solutionwas heated to reflux for 18 h and a second portion of K₂CO₃ (397 mg,2.87 mmol, 2 equiv) was then added followed by the addition of anotherportion of copper (I) iodide (54.6 mg, 0.287 mmol, 0.2 equiv). Thereaction mixture was heated to reflux for 18 h. The resulting mixturewas filtered through a celite pad and washed with isopropanol (10 mL).The filtrate was reduced in volume to ˜5 mL and 10N HCl (1.1 equiv) wasadded dropwise, with stirring, to the filtrate. The resulting slurry wascooled in an ice bath for 30 min before being filtered on a Buchnerfunnel to afford the HCl of the title compound as a pale yellow solid(110 mg, 21.7% yield). MS: (ES, m/z): 318 [M+H]⁺.

Step-3: Methyl(S)-3-(4-chlorophenyl)-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-(4-chlorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (20 mg, 0.056 mmol, 1 equiv), Et₃N (0.024 mL, 0.169 mmol,3 equiv), morpholine-4-carbonyl chloride (9.29 mg, 0.062 mmol, 1.1equiv), and MeCN (2 mL) were added to a 4-mL vial equipped with a stirbar and the resulting solution was stirred at room temperature for 4 h.The reaction was concentrated to dryness to afford the title compound asa colorless oil. MS: (ES, m/z): 431 [M+H]⁺.

Step-4:(S)-3-(4-Chlorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3-(4-chlorophenyl)-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(24.13 mg, 0.056 mmol, 1 equiv), NH₂OH (50% in water, 0.074 mL, 1.12mmol, 20 equiv), and aq. 1N NaOH (0.11 mL, 2 equiv) in a solution ofTHF/MeOH (4:1, 1.5 mL) were added to a 4-mL vial and the resultingsolution was stirred at room temperature overnight. The reaction mixturewas concentrated to dryness and purified by prep-HPLC (Column: XbridgePrep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% formic acid;Mobile Phase B: MeCN/0.1% formic acid; Flow rate: 23 mL/min; Gradient:0% B up to 35% B in 8 min; Detector: UV 254, 220 nm) to afford the titlecompound as a white solid (3.2 mg, 13.2% yield). MS: (ES, m/z): 432[M+H]⁺.

Example 10—Preparation of(S)-3-(3-chlorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-(3-chlorophenyl)-2-hydroxyethyl)amino)methyl)benzoate

(S)-2-Amino-2-(3-chlorophenyl)ethan-1-ol (250 mg, 1.20 mmol, 1 equiv),K₂CO₃ (664 mg, 4.81 mmol, 4 equiv), and MeCN (15 mL) were added to a40-mL vial equipped with a stir bar and the resulting slurry was cooledto 0° C. in an ice-water bath. A solution of methyl3-bromo-4-(bromomethyl)benzoate (370 mg, 1.20 mmol, 1 equiv) in MeCN (3mL) was added dropwise over 10 min while maintaining the internaltemperature at 0° C. The ice bath was removed and the resulting slurrywas allowed to slowly warm to room temperature. Stirring was continuedat room temperature for 16 h. The reaction was concentrated underreduced pressure to remove most of the MeCN and the concentrated mixturewas partitioned between EtOAc (10 mL) and H₂O (5 mL). The combinedorganic phases were separated and washed with brine (5 mL), dried overNa₂SO₄, filtered, and concentrated to afford the title compound as apale yellow oil (436 mg). MS: (ES, m/z): 399 [M+H]⁺.

Step-2: Methyl(S)-3-(3-chlorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-bromo-4-(((1-(3-chlorophenyl)-2-hydroxyethyl)amino)methyl)benzoate(436 mg, 1.09 mmol, 1 equiv) in isopropanol (5 mL) and K₂CO₃ (302 mg,2.19 mmol, 2 equiv) were added to a 40-mL vial equipped with a stir barfollowed by CuI (41.7 mg, 0.219 mmol, 0.2 equiv). The resulting solutionwas heated to reflux for 18 h. The resulting mixture was filteredthrough a celite pad and washed with isopropanol (10 mL). The filtratewas reduced in volume to ˜5 mL and 10N HCl (1.1 equiv) was addeddropwise, with stirring, to the filtrate. The resulting slurry wascooled in an ice bath for 30 min before being filtered on a Buchnerfunnel to afford the HCl salt of the title compound as a pale yellowsolid (75.6 mg, 19.5% yield). MS: (ES, m/z): 318 [M+H]⁺.

Step-3: Methyl(S)-3-(3-chlorophenyl)-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-(3-chlorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (22 mg, 0.062 mmol, 1 equiv), Et₃N (0.026 mL, 0.186 mmol,3 equiv), morpholine-4-carbonyl chloride (10.22 mg, 0.068 mmol, 1.1equiv), and MeCN (2 mL) were added to a 4-mL vial equipped with a stirbar and the resulting solution was stirred for 16 h at 50° C. Thereaction was concentrated to dryness to afford the title compound as apale yellow oil. MS: (ES, m/z): 431 [M+H]⁺.

Step-4:(S)-3-(3-Chlorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3-(3-chlorophenyl)-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(26.7 mg, 0.062 mmol, 1 equiv), NH₂OH (50% in water, 0.082 mL, 1.24mmol, 20 equiv), and aq. 1N NaOH (0.12 mL, 2 equiv) in a solution ofTHF/MeOH (4:1, 1.5 mL) were added to a 4-mL vial and the resultingsolution was stirred at room temperature overnight. The reaction wasconcentrated to dryness and purified directly by prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN/0.1% formic acid; Flow rate: 23 mL/min;Gradient: 15% B up to 65% B in 8 min; Detector: UV 254, 220 nm) toafford the title compound as a white solid (7.7 mg, 29% yield). ¹H-NMR(300 MHz, CDCl₃) δ(ppm): 8.01 (s, 1H), 7.14-7.44 (m, 7H), 5.23 (br s,1H), 4.96-5.42 (m, 1H), 4.23-4.72 (m, 3H), 3.63 (br s, 3H), 3.19 (br s,4H), 1.17-1.46 (m, 2H). MS: (ES, m/z): 432 [M+H]⁺.

Example 11—Preparation of(S)-3-(4-fluorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-(4-fluorophenyl)-2-hydroxyethyl)amino)methyl)benzoate

(S)-2-Amino-2-(4-fluorophenyl)ethan-1-ol (260 mg, 1.68 mmol, 1 equiv),K₂CO₃ (572 mg, 4.14 mmol, 3 equiv), and MeCN (15 mL) were added to a40-mL vial equipped with a stir bar and the resulting slurry was cooledto 0° C. in an ice-water bath. A solution of methyl3-bromo-4-(bromomethyl)benzoate (425 mg, 1.38 mmol, 1 equiv) in MeCN (3mL) was then added dropwise over 10 min while maintaining the internaltemperature at 0° C. The ice bath was removed and the resulting slurrywas allowed to slowly warm to room temperature. Stirring was continuedat room temperature for 16 h. The reaction mixture was concentratedunder reduced pressure to remove most of the MeCN and the concentratedmixture was partitioned between EtOAc (10 mL) and H₂O (5 mL). The phaseswere separated and the organic phase was washed with brine (5 mL), driedover Na₂SO₄, filtered, and concentrated to afford the title compound asa pale yellow oil (592 mg). MS: (ES, m/z): 383 [M+H]⁺.

Step-2: Methyl(S)-3-(4-fluorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-bromo-4-(((1-(4-fluorophenyl)-2-hydroxyethyl)amino)methyl)benzoate(592 mg, 1.55 mmol, 1 equiv) in isopropanol (5 mL) and K₂CO₃ (642 mg,4.65 mmol, 2 equiv) were added to a 40-mL vial equipped with a stir barfollowed by CuI (59 mg, 0.31 mmol, 0.2 equiv). The resulting solutionwas heated to reflux for 18 h. The reaction mixture was then filteredthrough a celite pad and washed with isopropanol (10 mL). The filtratewas reduced in volume to ˜5 mL and 10N HCl (1.1 equiv) was addeddropwise, with stirring, to the filtrate. The resulting slurry wascooled in an ice bath for 30 min before being filtered on a Buchnerfunnel to afford the HCl salt of the title compound as a pale yellowsolid (119.6 mg, 22.9% yield). MS: (ES, m/z): 302 [M+H]⁺.

Step-3: Methyl(S)-3-(4-fluorophenyl)-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl(S)-3-(4-fluorophenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (60 mg, 0.178 mmol, 1 equiv), Et₃N (0.087 mL, 0.622 mmol,3.5 equiv), morpholine-4-carbonyl chloride (0.025 mL, 0.213 mmol, 1.2equiv), and CH₂Cl₂ (2 mL) were added to a 4-mL vial equipped with a stirbar and the resulting solution was stirred at room temperature for 16 h.The reaction mixture was then washed with aq. 1N NaOH (1 mL). Theorganic layer was separated, dried over Na₂SO₄, filtered, andconcentrated to dryness to afford the title compound (131 mg). MS: (ES,m/z): 415 [M+H]⁺.

Step-4:(S)-3-(4-Fluorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Methyl(S)-3-(4-fluorophenyl)-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(131 mg, 0.316 mmol, 1 equiv), NH₂OH (50% in water, 0.418 mL, 6.32 mmol,20 equiv), and aq. 1N NaOH (0.63 mL, 2 equiv) in a solution of THF/MeOH(4:1, 1.5 mL) were added to a 4-mL vial and the resulting solution wasstirred at room temperature overnight. The reaction mixture was thenconcentrated to dryness and purified directly by prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN/0.1% formic acid; Flow rate: 23 mL/min;Gradient: 0% B up to 35% B in 8 min; Detector: UV 254, 220 nm) to affordthe title compound (58.4 mg, 44.5% yield). ¹H-NMR (300 MHz, CDCl₃)δ(ppm): 8.10 (br d, J=16.7 Hz, 1H), 7.18-7.40 (m, 4H), 6.85-7.18 (m,3H), 5.19 (br s, 2H), 4.37-4.71 (m, 3H), 4.28 (br s, 2H), 3.65-4.01 (m,1H), 3.58 (br s, 3H), 3.27-3.52 (m, 5H), 3.14 (br s, 4H), 2.78 (br s,1H), 1.25 (br s, 1H). MS: (ES, m/z): 416 [M+H]⁺.

Example 12—Preparation of(R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzoI[f][1,4]oxazepine-8-carboxamide and(S)—N-hydroxy-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzoI[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl3-bromo-4-(((2-hydroxy-1-(pyridin-3-yl)ethyl)amino)methyl)benzoate

A solution of 2-amino-2-(pyridin-3-yl)ethan-1-ol dihydrochloride (980mg, 4.64 mmol, 2 equiv) in MeCN (40 mL) was added to a 250-mLround-bottom flask followed by the portionwise addition of K₂CO₃ (1.29g, 9.33 mmol, 4 equiv). To this mixture was added a solution of methyl3-bromo-4-(bromomethyl)benzoate (713 mg, 2.32 mmol, 1 equiv) in MeCN (20mL) dropwise and with stirring. The resulting solution was stirredovernight at room temperature and then concentrated under vacuum. Theresidue was dissolved in 40 mL of water and extracted with EtOAc (3×60mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography (MeOH/CH₂Cl₂, 1:20) to afford the titlecompound as a light brown solid (380 mg, 43% yield). MS: (ES, m/z): 365[M+H]⁺.

Step-2: Methyl3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A solution of methyl3-bromo-4-((2-hydroxy-1-(pyridin-3-yl)ethylamino)methyl) benzoate (260mg, 0.71 mmol, 1 equiv) in isopropanol (8 mL) was added to a 10-mLsealed tube purged and maintained with an inert atmosphere of nitrogenfollowed by the portionwise addition of K₂CO₃ (147.5 mg, 1.07 mmol, 1.5equiv). To this mixture was added CuI (67.6 mg, 0.35 mmol, 0.5 equiv) inportions and the resulting solution was stirred overnight at 105° C. inan oil bath. The reaction mixture was cooled to room temperature with awater/ice bath and then concentrated under vacuum. The residue wasdissolved in EtOAc (80 mL) and washed with brine (3×30 mL), The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to afford the title compound as light yellowoil (210 mg) which was used to the next step without purification. MS:(ES, m/z): 285 [M+H]⁺.

Step-3: Methyl(R)-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand Methyl(S)-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.35 mmol, 1 equiv) in CH₂Cl₂ (2.5 mL) were added to an 8-mLvial followed by the addition of Et₃N (177.8 mg, 1.76 mmol, 5 equiv) andtriphosgene (52.1 mg, 0.18 mmol, 0.5 equiv) at 0° C. The mixture wasstirred for 30 min at room temperature and morpholine (61.2 mg, 0.70mmol, 2 equiv) was then added. The resulting solution was stirred for 2h at room temperature and then concentrated under vacuum. The crudeproduct was purified by flash-prep-HPLC (Column: C18, 40 g, 20-45 μm,100 Å; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate:80 mL/min; Gradient: 5% B to 30% B in 30 min; Detector: UV 254, 220 nm).The pH value of the collected fractions was then adjusted to 8 with aq.1N NaOH solution. The resulting solution was extracted with CH₂Cl₂(2×150 mL). The combined organic layers were dried over anhydrousNa₂SO₄, filtered, and concentrated under vacuum to afford the racemateof the title compounds as a white solid (40 mg, 29%). The racemate wasseparated by chiral prep-HPLC (Column: Phenomenex Lux Cellulose-4, AXIAPacked, 5 μm, 21.2×250 mm; Mobile Phase: MeOH; Flow rate: 20 mL/min;Detector: UV 254, 220 nm) to afford the single isomers of the titlecompounds as white solids. First eluting isomer, arbitrarily drawn asthe R isomer: (15 mg, 38% yield); second eluting isomer, arbitrarilydrawn as the S isomer: (18 mg, 45% yield). MS: (ES, m/z): 398 [M+H]⁺.

Step-4:(R)—N-Hydroxy-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamideand(S)—N-Hydroxy-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into 8-mL vials was added each of the separated isomers from Step 3 (15mg, 0.04 mmol; and 18 mg, 0.05 mmol; 1 equiv) in THF/MeOH (4:1, 2.5 mL),followed by aq. 1N NaOH (2 equiv) and NH₂OH (50% in H₂O, 60 equiv). Theresulting solution was stirred for 3 h at room temperature and the crudeproducts were purified by prep-HPLC (Column: Xbridge C18 OBD, 5 μm,19×250 mm; Mobile Phase A: Water/10 mM NH₄HCO₃; Mobile Phase B: MeCN;Gradient: 3% B to 30% B in 8 min; Detector: UV 254, 220 nm) to affordthe title compounds as white solids. Product from the reaction with thefirst eluting isomer of Step 3: (6.1 mg, 41% yield); ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.13 (br s, 1H), 9.01 (br s, 1H), 8.62 (s, 1H), 8.49(d, J=4.4 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.34-7.24(m, 2H), 5.27-5.26 (m, 1H), 4.70-4.61 (m, 3H), 4.51-4.48 (m, 1H),3.56-3.51 (m, 4H), 3.02-3.01 (m, 4H). Product from the reaction with thesecond eluting isomer of Step 3: (7.6 mg, 42% yield); ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 9.01 (br s, 1H), 8.62 (s, 1H), 8.50 (d, J=3.6 Hz, 1H),7.80 (d, J=7.6 Hz, 1H), 7.42-7.36 (m, 2H), 7.34-7.24 (m, 2H), 5.26-5.25(m, 1H), 4.70-4.61 (m, 3H), 4.51-4.77 (m, 1H), 3.56-3.48 (m, 4H),3.02-3.00 (m, 4H). MS: (ES, m/z): 399 [M+H]+:

Example 13—In Vitro Histone Deacetylase Assay

The enzymatic HDAC6 assay was performed using electrophoretic mobilityshift assay. Full length human recombinant HDAC6 protein was expressedin baculoviral system and purified by affinity chromatography. Theenzymatic reactions were assembled in 384 well plates and in a totalvolume of 25 μL in a reaction buffer comprising: 100 mM HEPES, pH 7.5,25 mM KCl, 0.1% bovine serum albumin, 0.01% Triton X-100, 1% DMSO (fromcompounds), 2 μM of the fluorescently labeled peptide substrate, andenzyme. The enzyme was added at a final concentration of 1 nM and thepeptide substrate RHKK(Ac)—NH2 was used. The compounds were tested at 12concentrations spaced by 3× dilution intervals. Negative control samples(0%−inhibition in the absence of inhibitor) and positive control samples(100%−inhibition) were assembled in replicates of four in each assayplate. The reactions were incubated at 25° C. and quenched by theaddition of 45 μL of termination buffer (100 mM HEPES, pH 7.5, 0.01%Triton X-100, 0.05% SDS).

The terminated assay plates were analyzed on LabChip® 3000 microfluidicelectrophoresis instrument (Perkin Elmer/Caliper Life Sciences). Thefluorescence intensity of the electrophoretically separatedde-acetylated product and substrate peptide was measured. Activity ineach sample was determined as the product to sum ratio (PSR): P/(S+P),where P is the peak height of the product peptide and S is the peakheight of the substrate peptide. Percent inhibition (P_(inh)) isdetermined using the following equation:P _(inh)=(PSR_(0%)−PSR_(inh))/(PSR_(0%)−PSR_(100%))*100,where PSR_(inh) is the product sum ratio in the presence of inhibitor,PSR_(0%) is the average product sum ration in the absence of inhibitor,and PSR_(100%) is the average product sum ratio in 100%−inhibitioncontrol samples. The IC₅₀ values of inhibitors were determined byfitting the %-inhibition curves with 4 parameter dose-response modelusing XLfit 4 software.

As set forth in Table 4, below, IC₅₀ values are defined as follows:IC50≤0.1 μM (+++); IC50>0.1 μM and <0.5 μM (++); IC50>0.5 μM (+).

TABLE 4 Inhibitory Concentration (IC₅₀) Values for RepresentativeCompounds against HDAC6. Activity COMPOUND NAME Range(R)-N-hydroxy-4-methyl-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-4-(4-methoxybenzyl)-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-3,4-diphenyl-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-methyl-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(4-methoxybenzyl)-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3,4-diphenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-((4-fluorophenyl)sulfonyl)-N-hydroxy-3-phenyl-2,3,4,5- ++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N8-hydroxy-N4,N4-dimethyl-3-phenyl-2,3- +++dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide(S)-N-hydroxy-4-(morpholine-4-carbonyl)-3-phenyl-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(4-methoxypiperidine-1-carbonyl)-3-phenyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(4-methylpiperazine-1-carbonyl)-3-phenyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-4-(4-acetylpiperazine-1-carbonyl)-N-hydroxy-3-phenyl- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(morpholine-4-carbonyl)-3-(4- +++(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-phenyl-4-(piperidine-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-3-phenyl-4-(pyrrolidine-1-carbonyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N4-cyclohexyl-N8-hydroxy-3-phenyl-2,3- +++dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide(S)-N8-hydroxy-3-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-2,3- +++dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide(S)-N8-hydroxy-N4,3-diphenyl-2,3- +++dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide(S)-N8-hydroxy-3-phenyl-N4-(pyridin-4-yl)-2,3- +++dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide(S)-N8-hydroxy-3-phenyl-N4-(pyridin-3-yl)-2,3- +++dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide(S)-N-hydroxy-4-(morpholine-4-carbonyl)-3-(p-tolyl)-2,3,4,5- +++tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-3-(4-chlorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-3-(3-chlorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(R)-N-hydroxy-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)- +2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-N-hydroxy-4-(morpholine-4-carbonyl)-3-(pyridin-3-yl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide(S)-3-(4-fluorophenyl)-N-hydroxy-4-(morpholine-4-carbonyl)- +++2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

EQUIVALENTS

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

The invention claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is O; X² isCR¹R², and X⁴ is C═O; X³ is CR^(1′)R^(2′); Y¹ and Y⁴ are not bonded to—C(O)NHOH and are each CR¹; one of Y² and Y³ is CR¹, and the other of Y²and Y³ is C—C(O)NHOH; L is selected from the group consisting of a bond,—(CR¹R²)_(n)—, —C(O)O—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, and—S(O)NR³—, wherein L is bound to the ring nitrogen through the carbonylor sulfonyl group; R is independently selected from the group consistingof —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆alkynyl, —C₃-C₈ cycloalkyl, —C₅-C₁₂ spirocyclyl, heterocyclyl,spiroheterocyclyl, aryl, and heteroaryl containing 1 to 5 heteroatomsselected from the group consisting of N, S, P, and O, wherein eachalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocyclyl,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more substituents selected from the groupconsisting of —OH, halogen, oxo, —NO₂, —CN, —R¹, —R², —OR³, —NHR³,—NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹,—S(O)NR³R⁴, —NR³S(O)R¹, heterocyclyl, aryl, and heteroaryl containing 1to 5 heteroatoms selected from the group consisting of N, S, P, and O;each R¹ and R² is independently, and at each occurrence, selected fromthe group consisting of —H, —R³, —R⁴, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,—C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O, —OH, halogen, —NO₂, —CN, —NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂R⁵,—S(O)₂(C₁-C₆ alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, or —(CHR⁵)_(n)NR³R⁴, whereineach alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or moresubstituents selected from —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³,—NHR³, —NR³R⁴, —S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵,—S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵, heterocyclyl, aryl, and heteroarylcontaining 1 to 5 heteroatoms selected from the group consisting of N,S, P, and O; each of R^(1′) and R^(2′) is independently, and at eachoccurrence, selected from the group consisting of H, aryl, andheteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O, wherein each aryl or heteroaryl isoptionally substituted with one or more substituents selected from thegroup consisting of —OH, halogen, —NO₂, oxo, —CN, —R³, —R⁵, —OR³, —NHR³,—NR³R⁴, —S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,—S(O)NR³R⁴, —NR³S(O)R⁵, heterocyclyl, aryl, and heteroaryl containing 1to 5 heteroatoms selected from the group consisting of N, S, P, and O,wherein at least one of R^(1′) or R^(2′) is not H; each R³ and R⁴ isindependently, and at each occurrence, selected from the groupconsisting of —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl,—C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroarylcontaining 1 to 5 heteroatoms selected from the group consisting of N,S, P, and O, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂(C₁-C₆ alkyl), —(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, and —(CHR⁵)_(n)N(C₁-C₆alkyl)₂, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore substituents selected from the group consisting of —OH, halogen,—NO₂, oxo, —CN, —R⁵, —O(C₁-C₆) alkyl, —NH(C₁-C₆) alkyl, —N(C₁-C₆alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NHC₁-C₆ alkyl, —C(O)C₁-C₆ alkyl,—CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, —S(O)R⁵, —S(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)R⁵, heterocyclyl, aryl, and heteroarylcontaining 1 to 5 heteroatoms selected from the group consisting of N,S, P, and O; or R³ and R can combine with the nitrogen atom to whichthey are attached to form a heterocycle or heteroaryl containing 1 to 5heteroatoms selected from the group consisting of N, S, P, and O,wherein each heterocycle or heteroaryl is optionally substituted with—R⁴, —OR⁴, or —NR⁴R⁵; R⁵ is independently, and at each occurrence,selected from the group consisting of —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,—C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl containing 1 to 5 heteroatoms selected from the groupconsisting of N, S, P, and O, —OH, halogen, —NO₂, —CN, —NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆ alkyl, —S(O)(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆ alkyl) and —(CH₂)_(n)N(C₁-C₆ alkyl)₂; and each n isindependently and at each occurrence an integer from 0 to
 6. 2. Thecompound of claim 1, wherein the compound is of the Formula IA:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2, wherein the compound is of the Formula IA-10:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein the compound is of the Formula IB

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim4, wherein the compound is of the Formula IB-4:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, wherein one of R^(1′) and R^(2′) is optionally substituted aryl andthe other of R^(1′) and R^(2′) is H.
 7. The compound of claim 6, whereinL is —C(O)NR³—.
 8. The compound of claim 7, wherein the R³ and R combinewith the nitrogen atom to which they are attached to form an optionallysubstituted heterocycle.
 9. The compound of claim 1, wherein one ofR^(1′) and R^(2′) is optionally substituted heteroaryl and the other ofR^(1′) and R^(2′) is H.
 10. The compound of claim 9, wherein L is—C(O)NR³—.
 11. The compound of claim 10, wherein the R³ and R combinewith the nitrogen atom to which they are attached to form an optionallysubstituted heterocycle.
 12. The compound of claim 6, wherein L is abond.
 13. The compound of claim 12, wherein R is an optionallysubstituted group selected from the group consisting of —C₁-C₆ alkyl,—C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl.
 14. The compoundof claim 13, wherein —C₁-C₆ alkyl is substituted with an optionallysubstituted group selected from the group consisting of aryl,heteroaryl, or —C₃-C₈ cycloalkyl.
 15. A pharmaceutical compositioncomprising a compound of claim 1, and a pharmaceutically acceptablecarrier.